Residual viremia (RV) is present in most if not all patients who are responding well to highly active antiretroviral therapy (HAART). It now appears that HAART reduces viremia to new steady state level that averages around 1 copy of HIV-1 RNA/ml of plasma. This steady state appears to persist indefinitely with no further decay. Because the half life of virions in the plasma is short (minutes to hours), the continued presence of free virus in the plasma of patients on HAART indicates ongoing virus production. Thus it is clear that the sources of RV must be understood if HIV-1 eradication is to be achieved. In the previous funding period, we have carried out the first study of intensification of a standard HAART regimen. We found that intensification fails to reduce RV, indicating that most of the RV results from release of virus from stable reservoirs of cells infected prior to the initiation of therapy. These results indicate that the theoretical potential of HAART to control viremia has already been reached and that further progress towards HIV eradication will require new strategies that directly target stable reservoirs. Through the clonal analysis of RV, we have also found that the RV there is at least one other source of RV in addition to the stable reservoir in resting CD4+ T cells. We now propose to continue studies of RV to obtain clones of replication- competent virus from the RV. This will provide direct evidence that the viruses constituting the RV are of potential clinical significance. In addition, in a new project prompted by the interest in our intensification study, we will study patients who have stable low level viremia in the range of 75-400 copies/ml. These patients currently represent a significant clinical dilemma. The presence of detectable viremia often triggers a change in regimen. However, it is possible that stable low level viremia reflects release of virus from stable reservoirs that are larger in some patients than in others. Thus we will carry out a detailed analysis of low level viremia in these patients in order to provide a molecular explanation for persistent low level viremia and to obtain additional insight into stable viral reservoirs. RELEVANCE (See instructions); Most pafients who are doing well on combination therapy for HIV infection have trace levels of free virus in the blood called residual viremia. We have shown that this residual viremia is due to the release of virus from stable reservoirs of infected cells that persist despite the presence of antiretroviral drugs. Progress towards HIV eradication will require the identification and elimination of these reservoirs.